title: RAGE is a nucleic acid receptor that promotes inflammatory responses to DNA.
abstract: Recognition of DNA and RNA molecules derived from pathogens or self-antigen is one way the mammalian immune system senses infection and tissue damage. Activation of immune signaling receptors by nucleic acids is controlled by limiting the access of DNA and RNA to intracellular receptors, but the mechanisms by which endosome-resident receptors encounter nucleic acids from the extracellular space are largely undefined. In this study, we show that the receptor for advanced glycation end-products (RAGE) promoted DNA uptake into endosomes and lowered the immune recognition threshold for the activation of Toll-like receptor 9, the principal DNA-recognizing transmembrane signaling receptor. Structural analysis of RAGE-DNA complexes indicated that DNA interacted with dimers of the outermost RAGE extracellular domains, and could induce formation of higher-order receptor complexes. Furthermore, mice deficient in RAGE were unable to mount a typical inflammatory response to DNA in the lung, indicating that RAGE is important for the detection of nucleic acids in vivo.
authors.affiliation: Department of Medicine, Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA 01605.
authors.forename: Cherilyn M
authors.initials: CM
authors.lastname: Sirois
authors.forename: Tengchuan
authors.initials: T
authors.lastname: Jin
authors.forename: Allison L
authors.initials: AL
authors.lastname: Miller
authors.forename: Damien
authors.initials: D
authors.lastname: Bertheloot
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Nakamura
authors.forename: Gabor L
authors.initials: GL
authors.lastname: Horvath
authors.forename: Abubakar
authors.initials: A
authors.lastname: Mian
authors.forename: Jiansheng
authors.initials: J
authors.lastname: Jiang
authors.forename: Jacob
authors.initials: J
authors.lastname: Schrum
authors.forename: Lukas
authors.initials: L
authors.lastname: Bossaller
authors.forename: Karin
authors.initials: K
authors.lastname: Pelka
authors.forename: Natalio
authors.initials: N
authors.lastname: Garbi
authors.forename: Yambasu
authors.initials: Y
authors.lastname: Brewah
authors.forename: Jane
authors.initials: J
authors.lastname: Tian
authors.forename: ChewShun
authors.initials: C
authors.lastname: Chang
authors.forename: Partha S
authors.initials: PS
authors.lastname: Chowdhury
authors.forename: Gary P
authors.initials: GP
authors.lastname: Sims
authors.forename: Roland
authors.initials: R
authors.lastname: Kolbeck
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Coyle
authors.forename: Alison A
authors.initials: AA
authors.lastname: Humbles
authors.forename: T Sam
authors.initials: TS
authors.lastname: Xiao
authors.forename: Eicke
authors.initials: E
authors.lastname: Latz
mesh_terms: D000818:Animals; D001483:Base Sequence; D002462:Cell Membrane / Q000378:metabolism; D018360:Crystallography, X-Ray; D004247:DNA / Q000737:chemistry / Q000378:metabolism*; D004705:Endocytosis; D011992:Endosomes / Q000378:metabolism; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D008024:Ligands; D008168:Lung / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D016328:NF-kappa B / Q000378:metabolism; D011014:Pneumonia / Q000378:metabolism* / Q000473:pathology*; D011485:Protein Binding; D055503:Protein Multimerization; D017434:Protein Structure, Tertiary; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000737:chemistry / Q000378:metabolism*; D055672:Static Electricity; D051217:Toll-Like Receptor 9 / Q000378:metabolism
chemical_list: D008024:Ligands; D016328:NF-kappa B; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D051217:Toll-Like Receptor 9; D004247:DNA